Acute stroke is one of the most under-treated serious diseases in the United States. A major challenge in the study of stroke is that most treatments effective in experimental animals have failed in humans. One possible explanation is that targets for protection have been identified in otherwise healthy animals upon which focal cerebral ischemia has been imposed. Type 2 diabetes that is often accompanied by hypertension is the most rapidly increasing risk factor for stroke and also increases the risk of hemorrhage and poor outcome of stroke. While it is known that the integrity of cerebral blood vessels is critical in the pathophysiology of stroke, targets to protect the vasculature from ischemic injury in the presence of preexisting vascular disease are yet to be identified. The objective of this application is to conduct feasibility studies to test our global hypothesis that diabetes-induced changes in the cerebral microvessel wall increase the risk of hemorrhage and augment ischemic injury. Two specific aims will test the subhypotheses that: 1) Chronic hyperglycemia promotes neovascularization and microvascular remodeling associated with increased expression/activity of the mediators of ischemia/reperfusion injury and decreased expression of proteins essential for extracellular matrix anchoring and integrity in cerebral microvessels, and 2) Diabetes-induced neovascularization prevents infarct expansion but alterations in vessel wall structure increase the risk for hemorrhage and thereby exacerbate neurovascular damage due to cerebral ischemia/reperfusion. Aim 1 will be achieved by critically evaluating vessel density and tortuosity as well as MMP expression/activity and determinants of microvascular integrity (VEGF, laminin and PECAM-1) in small cerebral vessels of control, diabetic GK and euglycemic GK rats. Completion of this Aim will determine to what extent chronic elevations in blood glucose modifies small vessel structure/density and the expression of key mediators of ischemia/reperfusion injury in the brain. Aim 2 will be achieved by measuring indices (infarct size, hematoma formation and tissue hemoglobin) of ischemic injury over a 24-h window after 3 h middle cerebral artery occlusion (MCAO)-reperfusion in control, diabetic GK and euglycemic GK rats. Completion of this Aim will determine the impact of diabetes (chronic hyperglycemia) on the development of hemorrhage and overall magnitude of ischemic injury. At the completion of the above experiments, we expect to have a full understanding of the influence of diabetes on ischemic injury mediators that lead to the destruction of the cerebral blood vessel. Identification of causal factors and molecular mechanisms responsible for disruption of vascular integrity in diabetes will advance stroke treatment by reducing the risk of hemorrhage and improve stroke outcome. [unreadable] [unreadable] [unreadable]